ACPA-negative RA Research Articles

A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

IntroductionRheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying...

Parity in young women associates with ACPA-negative RA

Parity in young women associates with ACPA-negative RA

HLA-C alleles confer risk for anti-citrullinated peptide antibody-positive rheumatoid arthritis independent of HLA-DRB1 alleles

The MHC exerts the greatest contribution to RA susceptibility, where certain HLA-DRB1 alleles confer the greatest risk. Interestingly, there is evidence for more risk factors in the MHC with regions surrounding the HLA class I loci, but whether these antigen-presenting loci could be causal risk variants has not been directly investigated. In this study we investigate the HLA association by direct genotyping of the HLA loci. Nine hundred and fifty RA patients and 933 healthy controls were genotyped for HLA-A, -B and -C. Eleven single-nucleotide polymorphisms (SNPs) and one insertion/deletion in the MHC were also included. Conditional logistic regression analyses were performed separately in ACPA-positive and -negative RA to identify the strongest susceptibility locus and additional risk loci. In ACPA-positive RA, the most significantly associated locus was HLA-DRB1 (P = 1.58 × 10(-54)), with SE alleles being predisposing. After controlling for HLA-DRB1, the HLA-C locus was found to confer susceptibility (P = 2.32 × 10(-9)), particularly, the HLA-C*03 allele. Also, in ACPA-negative RA, HLA-DRB1 was the most significant locus (P = 7.22 × 10(-9)), but with other risk alleles (particularly DRB1*03). A possible independent involvement of HLA-C was also observed for ACPA-negative RA (P = 0.02). HLA-DRB1 was the major MHC risk locus in both ACPA-positive and ACPA-negative RA, but with allelic risk heterogeneity. Joint analyses of the HLA class I loci together with previously proposed SNP associations pointed at HLA-C as a second susceptibility locus in ACPA-positive RA.

OP0149 The Association Between Parity and Rheumatoid Arthritis: Results from the Swedish Eira Study

BackgroundRheumatoid arthritis (RA) is more common among women than among men and the gender difference in incidence seems to be highest before menopause (1). The importance of hormonal/reproductive factors has...

OP0083 Comparison of synovial tissue cytokine mrna profiles in very early arthritis patients with divergent outcomes

BackgroundIn the earliest clinically apparent phases of arthritis, it is difficult to distinguish patients who will develop RA from those whose disease will resolve. We hypothesised that synovial tissue cytokine...

OP0087 Use of Moist Snuff and the Risk of Developing Rheumatoid Arthritis; Results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis Study

BackgroundSmoking is the major known environmental risk factor for RA, and notably this risk factor is exclusively seen in ACPA-positive RA. Whether this increased risk is due to nicotine or...

Anti-citrullinated protein antibodies in rheumatoid arthritis: a bridge between genetic predisposition and autoimmunity

Anti-citrullinated protein antibodies in rheumatoid arthritis: a bridge between genetic predisposition and autoimmunity

Comparison of synovial tissue cytokine mRNA profiles in very early arthritis patients with divergent outcomes

Backgroundand objectivesIn the earliest clinically apparent phases of arthritis, it is difficult to distinguish patients who will develop RA from those whose disease will resolve. The authors hypothesised that synovial...

The contribution of genetic risk factors other than the HLA shared epitope alleles to the genetic variance of rheumatoid arthritis

ObjectiveGenetic factors explain 66% of susceptibility to rheumatoid arthritis, but it is unclear how much of this genetic risk can be explained by the genetic risk factors known to date....

ACPA-Negative RA Up in First Postpartum Year

ACPA-Negative RA Up in First Postpartum Year

A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) can be divided into two major subsets based on the presence or absence of antibodies to citrullinated peptide antigens (ACPA). Until now, data from genome-wide association studies...

Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis

Objectives. ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non-RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion.Methods. We genotyped HLA-DRB1 alleles for 574 ACPA-positive RA, 185 ACPA-negative RA (including 97 erosive RA) and 1508 healthy donors. We also tested whether HLA-DR SE is associated with RF-negative or ANA-negative RA.Results. ACPA-negative RA with apparent bone erosion was not associated with SE, supporting the idea that ACPA-negative RA is genetically distinct from ACPA-positive RA. We also tested whether these subsets are based on autoantibody-producing activity. In accordance with the ACPA-negative RA subset, the RF-negative RA subset showed a clearly distinct pattern of association with SE from the RF-positive RA. In contrast, ANA-negative as well as ANA-positive RA was similarly associated with SE, suggesting that the subsets distinguished by ACPA are not based simply on differences in autoantibody production.Conclusions. ACPA-negative erosive RA is genetically distinct from ACPA-positive RA.

The impact of HLA-DRB alleles on the subclass titres of antibodies against citrullinated peptides

The association between HLA-DR haplotypes and RA have been well established. However, the molecular mechanisms of how HLA mediates susceptibility and/or progression of the disease remain elusive. We therefore turned to the RA-specific antibodies directed against citrullinated peptide antigens (ACPAs) and investigated the association between HLA-DRB1 shared epitope (SE) alleles and the IgG subclass titres of cyclic citrullinated peptide (CCP)- and mutated citrullinated vimentin (MCV)-specific antibodies. One hundred and twenty-seven RA patients were typed for their HLA-DRB1 haplotypes applying low resolution and alleles potentially carrying the SE were sequenced. All patients' sera were analysed by ELISA for the presence of ACPA and 77 patients positive for CCP-specific antibodies were further analysed for the respective IgG subclasses. Subclass titres were then correlated to the presence of a SE. Finally, all patients were screened for the HLA-DRB4-associated splice variant. We found a gene dosage effect of the HLA-DRB1*04-associated SE on both the MCV- and CCP-specific IgG3 levels. The HLA-DRB4-associated splice variant accumulates in ACPA-negative RA patients. Both the dose-dependent increase in IgG3 among ACPA and the accumulation of the splice variant in ACPA-negative patients imply differential expression of the HLA alleles as the mechanism contributing to the susceptibility and/or disease progression of RA. The preponderance of IgG3 hints at a skewing towards a Th1 response and is reminiscent of increased signal strengths at the immunological synapse. Likewise, the abrogation of HLA-DRB4 expression due to the splice variant reduces the signal strength and seems to protect from ACPA development.